Grafting of fetal ventromesencephalic (VM) tissue to the nigral region of unilaterally 6-OHDA-lesioned animals in conjunction with GDNF injection that bridges the nigra and striatum, restores nigrostriatal tyrosine hydroxylase (TH) immunoreactivity. We investigated whether a herpes simplex virus (HSV) amplicon vector encoding GDNF (HSVgdnf) induces a similar restoration in hemiparkinsonian rats. Adult rats were anesthetized and unilaterally injected with 6-OHDA into the medial forebrain bundle. The completeness of lesions was tested by measuring amphetamine-induced rotation. One month after 6-OHDA administration, fetal VM tissues were grafted into the lesioned nigral area followed by injection of HSVgdnf or HSVlac (control) along a tract from nigra to striatum. Most animals that received transplantation and HSVgdnf injection showed a reduction in amphetamine-induced rotation three months after grafting. Animals that received HSVlac showed no reduced rotation. Immunocytochemistry revealed TH-positive neurons and fibers in the nigra and striatum, respectively, after HSVgdnf injection with grafting. No immunoreactivity was observed in grafted, HSVlac injected animals. These results indicate that fetal nigral transplantation and HSVgdnf injection may restore the nigrostriatal DA pathway in the Parkinsonian animals and supports that trophic activity of GDNF on midbrain DA neurons may be provided by HSV amplicon vectors.